The Streptococci bacteria are a pathogenic genera of microorganisms which have been associated with a wide variety of infectious disorders including suppuration, abscess formation, a variety of pyogenic infections, and septicemia. In particular, Streptococcus pyogenes (a group A streptococci, or GAS) is a prominent pathogen which causes skin and mucous membrane infections, as well as deep-seated connective tissue infections and severe, sometimes fatal, septicemia. Like many other pathogens, in order to infect the human host successfully, GAS must have the ability to adjust the expression of its virulence factors according to the varying conditions of different anatomical sites.
In GAS, the expression of several virulence factors is positively regulated at the level of transcription by the Mga regulator. See Perez-Casal et al. (1991); Chen et al., 1993; Podbielski et al. (1995) and (1996). Regulated genes include M and M-related proteins (phagocytosis resistance, eukaryotic cell interactions), fibronectin-related proteins (serum opacity factor). Speβ (protease) and c5a peptidase (inactivation of complement factor c5a). Recent evidence has demonstrated that, in addition to iron levels, pH, CO2, and temperature (see Caparon et al., 1992; Podbielski et al., 1992; Okada et al., 1993; McIver et al., 1995) and activity of the Mga regulator is associated with logarithmic and late logarithmic growth phase. See McIver et al. (1997).
Another regulator in Streptococcus is RofA, a positive transcriptional regulator of the fibronectin-binding protein (prtF) (see Fogg et al., 1994 and 1997) that promote bacterial attachment to the host extracellular matrix (see Hanski et al., 1992; and Van Heyningen et al., 1993). In contrast to Mga-controlled genes, RofA positively regulates prtF transcription as well as its own transcription in response to increased levels of O2. By a potentially independent mechanism, transcription of prtF is also induced in response to intracellular superoxide levels (see Gibson et al., 1996).
These data have suggested differential expression of eukaryotic cell-binding proteins such as RofA-dependent prtF and Mga-dependent emm in response to O2 and CO2 partial pressures. These observations have led to the proposal that these regulators may influence the expression of proteins important for the attachment of GAS in different in vivo environments such as superficial Langerhans cells or subsurface keratinocytes (Okada et al. 1994; 1995). As has been observed with regard to other bacterial species, the attachment of bacteria to host cells or implanted biomaterials is generally initiated through “extracellular matrix proteins,” or ECM's, which generally refer to such general families of macromolecules, collagens, structural glycoproteins, proteoglycans and elastins, including fibronectin, and fibrinogen, that provide support and modulate cellular behavior. However, the precise role of the bacteria's ability to bind to these extracellular matrix proteins and the knowledge of how to best utilize this information in order to prevent streptococcal infection has not yet been fully determined.
Moreover, outside of the two regulators RofA and Mga, very little is known with regard to environmentally dependent virulence gene expression in GAS, and thus there has been very limited information with regard to the regulation and inhibition of the extracellular matrix proteins that are responsible for the attachment and infection caused by GAS. In light of the extremely severe nature of the bacterial infections caused by the Streptococcal bacteria, it is extremely important to make a determination of which specific proteins are responsible for attachment to the surface of targeted cells, and to be able to use this information in order to develop vaccines and other biological agents which can be used to treat or prevention the severe infections associated with group A streptococci.